The process by which the mammalian immune system recognizes and reacts to foreign or alien materials is a complex one. An important facet of the system is the T lymphocyte, or “T cell” response. This response requires that T cells recognize and interact with complexes of cell surface molecules, referred to as human leukocyte antigens (“HLA”), or major histocompatibility complexes (“MHCs”), and peptides. The peptides are derived from larger molecules which are processed by the cells which also present the HLA/MHC molecule. See in this regard Male et al., Advanced Immunology; (J.P. Lipincott Company, 1987), especially chapters 6-10. The interaction of T cells and HLA/peptide complexes is restricted, requiring a T cell specific for a particular combination of an HLA molecule and a peptide. If a specific T cell is not present, there is no T cell response even if its partner complex is present. Similarly, there is no response if the specific complex is absent, but the T cell is present. This mechanism is involved in the immune system's response to foreign materials, in autoimmune pathologies, and in responses to cellular abnormalities. Much work has focused on the mechanisms by which proteins are processed into the HLA binding peptides. See, in this regard, Barinaga, Science 257: 880 (1992); Fremont et al., Science 257: 919 (1992); Matsumura et al., Science 257: 927 (1992); Latron et al., Science 257: 964 (1992). Also see Engelhard, Ann. Rev. Immunol. 12: 181-207; (1994).
The mechanism by which T cells recognize cellular abnormalities has also been implicated in cancer. For example, in PCT application PCT/US92/04354, filed May 22, 1992, published on Nov. 26, 1992, and incorporated by reference, a family of genes is disclosed, which are processed into peptides which, in turn, are expressed on cell surfaces, which can lead to lysis of the tumor cells by specific CTLs cytolytic T lymphocytes, or “CTLs” hereafter. The genes are said to code for “tumor rejection antigen precursors” or “TRAP” molecules, and the peptides derived therefrom are referred to as “tumor rejection antigens” or “TRAs”. See Traversari et al., Immunogenetics 35: 145 (1992); van der Bruggen et al., Science 254: 1643 (1991), for further information on this family of genes. Also, see U.S. Pat. No. 5,342,774.
In U.S. Pat. No. 5,405,940, the disclosure of which is incorporated by reference, it is explained that the MAGE genes code for proteins which are processed to nonapeptides which are then presented by an HLA-A1; molecule. The reference teaches that given the known specificity of particular peptides for particular HLA molecules, one should expect a particular peptide to preferably bind to one HLA molecule. This is important, because different individuals possess different HLA phenotypes. As a result, while identification of a particular peptide as being a partner for a specific HLA molecule has diagnostic and therapeutic ramifications, these are only relevant for individuals with that particular HLA phenotype. There is a need for further work in the area, because cellular abnormalities are not restricted to one particular HLA phenotype, and targeted therapy requires some knowledge of the phenotype of the abnormal cells at issue.
In U.S. Pat. No. 5,629,166; filed incorporated by reference, the fact that the MAGE-1; expression product is processed to a second TRA is disclosed. This second TRA is presented by HLA-C clone 10; molecules. The disclosure shows that a given TRAP can yield a plurality of TRAs. Also, see U.S. Pat. No.5,554,506, incorporated by reference, teaching peptides which bind to HLA-A2.
U.S. Pat. Nos. 5,530,096; and 5,487,934; incorporated by reference herein teach that tyrosinase, a molecule which is produced by some normal cells (e.g., melanocytes), is processed in tumor cells to yield peptides presented by HLA-A2; molecules.
In U.S. patent application Ser. No. 08/032,978, filed Mar. 18, 1993 (now U.S. Pat. No. 5,620,886), and incorporated by reference in its entirety, a second TRA, not derived from tyrosinase is taught to be presented by HLA-A2 molecules. The TRA is derived from a TRAP, but is coded for by a non-MA GB gene. This disclosure shows that a particular HLA molecule may present TRAs derived from different sources.
In U.S. Pat. No. 5,571,711, filed Jun. 17, 1993 and incorporated by reference herein, an unrelated tumor rejection antigen precursor, the so-called “BAGE” precursor, is described. The BAGE precursor is not related to the MAGE family.
A futher family of genes which are processed into tumor rejection antigens is taught by U.S. Pat. Nos. 6,610,013 and 5,648,226, as well as patent applications Ser. Nos. 08/531,662 and 08/602,039, filed on Sep. 21, 1995 and Feb. 15, 1996 respectively, now U.S. Pat. Nos. 5,858,689 and 6,069,001 respectively, and U.S. patent applications Ser. No. 08/669,161 (now U.S. Pat. No. 6,013,481) and Ser. No. 09/012,818, filed on Jun. 24, 1996 and Jan. 23, 1998, respectively. All of these applications are incorporated by reference. They reveal that there is a family of genes, the “GAGE” genes, which are related to each other. Six members of the GAGE family are described in these references.
It has now been found that there are at least two further members of the GAGE family, referred to hereafter as GAGE-7 and GAGE-8. These genes, as well as other aspects of the inventions, will be described in detail in the disclosure which follows.